Modulation of membrane organic transporters for enhanced drug uptake by reactive oxygen species (ROS)

• Applicant: Professor Dr. Sander Bekeschus
• Subject Area: Pharmacology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 506635689

Cancer is a systematic evolution of malignant cells with acquired failures to halt disease progression. The incidence of cancer continues to rise, with 14.1 million new cases every year. Melanoma has seen a continuous and dramatic incidence in the last decade, with 13.1 new cases per year per 100,000 men in Europe. Alternatively, non-melanoma skin cancer (NMSC), including squamous cell carcinoma (SCC) and basal cell carcinomas (BCC), has an incidence 18-20 times higher than that of melanoma. For decades, clinical trials with single regimen chemotherapy have failed to show its efficacy in melanoma, but with the development of inhibitors of activating BRAFV600E mutations and immunotherapy against, for instance, PD-1 and PD-L1, better clinical outcomes in melanoma patients were . However, a subset of patients with aggressive disease develops resistance to all existing therapies leading to fatality. This could be due to the tumor cells' clonal evolution, leading to therapy resistance by accumulating novel somatic driver mutations. Hence, there is a constant need for novel therapeutic strategies tailored against drug resistance, especially regarding the epigenetic disguise of essential genes facilitating drug sensitivity.Cold physical plasma has gained considerable importance in medicine due to its selective targeting of multiple tumor cells in vitro and in vivo. Significantly, this novel medical technology has been recently described to contribute to overcoming drug resistance in tumor cells. Mechanistically, the biomedical effects of cold physical plasma exposure are achieved by generating a plethora of reactive oxygen and nitrogen species (ROS/RNS), leading to mitochondria and endoplasmic reticulum dysfunction and subsequent tumor cell apoptosis. Recently, we have shown that this multi-ROS treatment upregulates the expression of organic cation solute carrier SLC22A16 in SK-MEL-28 cells leading to enhanced uptake of anthracyclines. In a preliminary screen, we identified that ROS treatment induces the expression of various transporters involved in drug uptake across multiple tumor cell lines. The aim of the current study is i) to determine ROS-induced expression of organic cation solute carrier (SLC), organic anion solute carrier (SLCO), and ATP-binding cassette (ABC) families of transporters in representative skin cancer cell lines with ROS treatment), ii) to identify the redox-dependent signaling mechanisms involved in the expression of the transporters, and iii) to demonstrate reversal of drug resistance in tumor cells and tumors. Our objectives will help mitigate drug resistance in cutaneous tumors due to its direct access to plasma treatment in existing treatment regimens.

• DFG Programme: Research Grants